Derivatives of indole and method for the production thereof



United States I atent O DERIVATIVES OF INDOLE AND METHOD FOR THEPRODUCTION THEREOF Jacob Finkelstein, East Paterson, and John Lee, EssexFells, N. J., assignors to Holfmann La Roche Inc., Roche Park, Nutley,N. 1., a corporation ofNew Jersey No Drawing. Application March 28,1952,

Serial No. 279,254

7 Claims. (Cl. 260-240) This invention relates to the production of1'-methyl- 2-[B-S-indoyl)ethyllpiperidine and ethyl 1-methyl-6-[,3-(3-indolyl)ethyllnipecotate which can also be designated as3-carbethoxy-1-methyl-6-[fi-(3-indoyl)ethyl]p1- peridine and saltsthereof. The novel compounds are oxytocics, having activity related tothat of the ergot alkaloids, for example, ergometrine.

The compounds can be synthesized by reacting indole- 3-aldehyde I withthe corresponding picolinium methyl quaternary salts, for example, witha-picoline methiodide II (R=H, X iodide), whereupon l-methyl-2-[B-(3-indolyl)vinyl]pyridinium iodide III (R=H, X-=iodide) is obtained; orwith 3-carbethoxy-1,6-dimethylpyridinium p-toluenesulfonate II(R=COOC2H5, X--p-toluenesulfonate), whereupon3-carbethoxy-1-methyl-6-[FMS-indolyl)vinyl]pyridinium p-toluenesulfonateIII CH (Elfin works III I II

CHn-CH i N HI The following examples will serve to illustrate theproduction of the intermediates as well as the final products. Theintermediates are also embraced within the scope of our invention.

EXAMPLE 1 (a) 1methyl2-[,8-(3-indolyl)vinyllpyridinium iodide Asuspension of 11.0 grams of a-picoline methiodide and 6.5 grams ofindole-3-aldehyde in 25 cc. of absolute alcohol, containing 2 cc. of drypiperidine, was refluxed.

As the mixture warmed up, the reaction product dissolved, and after 10minutes of refluxing, a crystalline product P. of 138-140" C.

lCC

, 2' began to form. The refluxing was continued for an additional hourand cooled. The product was collected and purified by recrystallizationfrom methanol. The 1-methy1-2-[B*(3-indolyl)vinyl] pyridinium iodidemelted at 265-267 C-. with decomposition. 1 1

(b) 1 -methyl-2- [fi-(S-indolyl) ethyl] piperidine A suspension of 41grams of 1-methyl-2- [,8-(3-indolyl)- vinylJpyridinium iodide in 1 literof 95% alcohol containing 100 mg. of platinum oxide catalyst was reducedwith hydrogen at C. under 200 lbs. per square inch pressure. Thereduction proceeded at a rapid rate and came to a stop when thetheoreticalamount of hydrogen was absorbed. The reddish solution wasfiltered 'from the catalyst and concentrated onthe steamf'bath toa smallvolume after the solution was made' alkaline to phenolphthalein withdilute sodium hydroxide. The oil thus produced was extracted with ether,the ether extract was dried, concentrated, and the colorless crystallineresidue was purified by recrystallization from benzene. The 1-methyl-2-[,B-(3-indolyl)ethyl]piperidine hada M.

The methiodide thereof was prepared by refiuxing a benzene solutionthereof with methyl iodide. Recrystallized from methanol, the colorlesscrystals of 31-methyl-2-[i3(3-indolyl)ethyl]piperidine methiodideacquired a pinkish cast,"M. P. 246 248 C.

EXAMPLE 2 (a) 3-carbethoxy-1,fi-dimethylpyridinium iodide (b)3-carbeth0xy-1-methyl-6-[B-(3-indolyl)vinyl]- pyridinium iodide Amixture of 5.5 grams of 3-carbethoxy-l,6-dimethylpyridinium iodide, 2.6grams of indole-3-aldehyde inlS cc. of absolute alcohol, and 1 cc. ofdry piperidine was refluxed. Reaction took place very quickly, and a red45 crystalline product soon formed. The reaction was ter minated afterone-half hour. The product, B-carbethoxy-1-methyl-6-[fl-(3-indolyl)vinyl]pyridinium iodide melted at 260-265 C.

EXAMPLE 3 (a) 3-carbethoxy-1-methyl-6-[B-(3-indolyl)vinyl]- pyridiniump-toluenesulfonate A solution of 18.6 grams of methyl-p-toluenesulfonateand 16.5 grams of ethyl 6-methylnicotinate was refluxed in dry xylenefor 1 hour and cooled. The xylene was decanted and the residuetriturated with acetone to oh- 0 tain crystalline3-carbethoxy-1,6-dimethylpyridinium ptoluene sulfonone, M. P. -122 C.

A solution of 7.25 grams of indole-3-aldehyde and 17.6 grams of3-carbethoxy-1,6-dimethylpyridinium ptoluenesulfonate in 50 cc. ofabsolute alcohol, and 1 cc. of dry piperidine, was refluxed for 3 hours.A red crystalline substance was obtained. The substance wasrecrystallized from 50% alcohol-water mixture. 3 carbethoxy l-methyl-[fi-(3=indolyl)vinyllpyridiniurn .ptoluenesulfonate was obtained asbrown glistening crystals, M. P. 294297 C. with decomposition.

(b) Ethyl-1 -methyl-6- [,8 (3-indoiyl ethyl J nipecomte ydroch loride Asuspension of 14 grams of 3-carbethoXy-l-methyl-6-Efi-(-3-indolyl)vinyllpyridinium p toluenesulfonate :in 300 cc. of 95%alcohol was reduced with hydrogen at 50 C. under 200 lbs. pressure persquare inch in the presence of 100 mg. of platinum oxide catalyst. Theclear colorless solution which resulted was concentrated in vacuo undernitrogen. The residue was treated with water, made alkaline with Nsodium hydroxide solution, and the oil, comprising ethyl -lmethyl-6-'[,3-(3-indo1yl)- ethyllnipecotate was extracted with ether.The ether solution was thoroughly dried and saturated with dry hydrogenchloride gas to produce the colorless hydrochloride. Uponcrystallization from ethanol, the ethyll-tnethyl-6-[13-(3-indolyl)ethylilnipecotate hydrochloride melted at193-195" C.

We claim:

1. A compound selected from the group consisting of those having theformula References Cited in the file of this patent UNITED STATESPATENTS Number Name 7 Date 2,355,659 Lee et al. Aug. 15, 1944 2,499,612Brooker et al. Oct. 22, 1 946 2,558,777 Papa et al. July 3, .1951

OTHER REFERENCES Chem. Abstracts, vol. 36, col. 7240 (1942). Aklgermanet al., Recueil des 1717auvaux Chimiques, vol. 70, pp. 899-916 (November1951).

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULA